The instant invention relates to the use of dihydroxy open acid statins and salts and esters thereof, which are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, in such a way so as to minimize their in vivo lactonization, and to a particular crystalline hydrated form of the calcium salt of dihydroxy open acid simvastatin referred to herein as compound I.
It has been clear for several decades that elevated blood cholesterol is a major risk factor for coronary heart disease (CHD), and many studies have shown that the risk of CHD events can be reduced by lipid-lowering therapy. Prior to 1987, the lipid-lowering armamentarium was limited essentially to a low saturated fat and cholesterol diet, the bile acid sequestrants (cholestyramine and colestipol), nicotinic acid (niacin), the fibrates and probucol. Unfortunately, all of these treatments have limited efficacy or tolerability, or both. With the introduction of lovastatin (MEVACOR(copyright); see U.S. Pat. No. 4,231,938), the first inhibitor of HMG-CoA reductase to become available for prescription in 1987, for the first time physicians were able to obtain comparatively large reductions in plasma cholesterol with very few adverse effects.
In addition to the natural fermentation products, mevastatin and lovastatin, there are now a variety of semi-synthetic and totally synthetic HMG-CoA reductase inhibitors, including simvastatin (ZOCOR(copyright); see U.S. Pat. No. 4,444,784), pravastatin sodium salt (PRAVACHOL(copyright); see U.S. Pat. No. 4,346,227), fluvastatin sodium salt (LESCOL(copyright); see U.S. Pat. No. 5,354,772), atorvastatin calcium salt (LIPITOR(copyright); see U.S. Pat. No. 5,273,995) and cerivastatin sodium salt (also known as rivastatin; see U.S. Pat. No. 5,177,080). The structural formulas of these and additional HMG-CoA reductase inhibitors, are described at page 87 of M. Yalpani, xe2x80x9cCholesterol Lowering Drugsxe2x80x9d, Chemistry and Industry, pp. 85-89 (Feb. 5, 1996). The HMG-CoA reductase inhibitors described above belong to a structural class of compounds which contain a moiety which can exist as either a 3-hydroxy lactone ring or as the corresponding ring opened dihydroxy open-acid, and are often referred to as xe2x80x9cstatins.xe2x80x9d An illustration of the lactone portion of a statin and its corresponding open-acid form is shown below. 
Salts of the dihydroxy open-acid can be prepared, and in fact, as noted above, several of the marketed statins are administered as the dihydroxy open acid salt forms. Lovastatin and simvastatin are marketed worldwide in their lactonized form. Lovastatin is shown as structural formula II, and simvastatin is shown as structural formula III, below. 
The lactonized forms of the statins are not active inhibitors of HMG-CoA reductase, but the dihydroxy open acid forms are. It is known that condensation of the dihydroxy open acid form of statins to the corresponding lactonized form occurs under acidic conditions, that is at about pH 4 or under. Therefore, due to the low gastric pH of the stomach, a statin conventionally administered by oral dosing in its lactone form will remain largely in its lactone form in the stomach. The vast majority of the drug will still be in the lactone form at the time of absorption from the intestine following oral dosing with the lactone. After absorption, the lactone enters the liver and it is in the hepatocytes that the lactone can be metabolized to the active open acid form, a reaction catalyzed by two hepatic esterases or xe2x80x9clactonases,xe2x80x9d one which is in the cytosolic and the other in the microsomal fraction. Once in the blood there is an additional plasma esterase which can also hydrolyze the lactone to the open acid. There may be some minimal chemical, i.e., non-enzymatic, hydrolysis that occurs in blood or in the liver; however, at the pH in blood and liver, there should not be any lactonization, i.e., conversion of open acid back to the lactone.
A statin conventionally administered by oral dosing in its dihydroxy open acid form or a pharmaceutically acceptable salt or ester thereof will tend to convert to its lactone form in the acidic environment of the stomach, so that a mixture of the open ring and the corresponding closed ring forms will co-exist there. For example, see M. J. Kaufman, International Journal of Pharmaceutics, 1990, 66(December 1), p. 97-106, which provides hydrolysis data that are used to simulate the extent of drug degradation that occurs in acidic gastric fluids following oral administration of several structurally related hypocholesterolemic agents, including simvastatin and lovastatin, and also see A. S. Kearney, et al., Pharmaceutical Research, 1993, 10(10), p. 1461-1465, which describes the interconversion kinetics and equilibrium of CI-981 (atorvastatin in its free acid form). Therefore, even after conventional oral dosing with a dihydroxy open acid statin or a salt or ester thereof, a mixture of the open acid and the corresponding lactone form of the drug could exist by the time of absorption from the intestine.
The preparation of the naturally occurring compound lovastatin and the semi-synthetic analog simvastatin leads to a mixture of the lactone and the open-ring dihydroxy acid forms. Several procedures have been published describing ways to make simvastatin from lovastatin, and most proceed through a lactone ring opening step at some point in the process and sometimes formation of a salt at the resulting carboxy acid, and end with a ring-closing step in order to make the final simvastatin product. For example, U.S. Pat. No. 4,820,850 describes a process for making simvastatin which involves opening the lactone ring of lovastatin and forming an alkyl-amide at the resulting carboxy acid, followed by protection of the two hydroxy groups and methylation of the 8xe2x80x2 acyl sidechain. After the methylation step, the hydroxy protecting groups are removed, the amide is hydrolyzed to the free acid and an ammonium salt of the free acid is formed, followed by a step to re-lactonize the ring. In U.S. Pat. No. 4,444,784, the 8xe2x80x2-acyl sidechain of lovastatin is removed and the lactone ring opened in the first step, followed by re-lactonization of the ring and protection of its hydroxy group. Next, the 8xe2x80x2 position is acylated to introduce the simvastatin sidechain and a deprotection step is performed to obtain the simvastatin final product. In another process disclosed in U.S. Pat. No. 4,582,915, the potassium salt of the ring opened form of lovastatin is methylated at the 8xe2x80x2 acyl sidechain, the free acid is then re-generated, and the dihydroxy open acid moiety is re-lactonized.
Since becoming available, millions of doses of simvastatin have been administered and these drugs have developed an excellent safety record. However, as noted in the Physician""s Desk Reference (PDR), in rare instances myopathy has been associated with the use of all statins, including simvastatin. The mechanism for statin-related myopathy is currently poorly understood. It is also known that many drugs, including certain statins such as simvastatin, are metabolized in the liver and intestine by the cytochrome P450 3A4 (CYP 3A4) enzyme system. As also noted in the PDR, there are adverse drug interaction concerns if a potent inhibitor of CYP3A4, such as itraconazole, and a CYP3A4-metabolized statin are used together, and some cases of myopathy were found to have occurred in patients taking such a drug combination. Simvastatin has been administered to over 20 million patients worldwide in the past 11 years and has been demonstrated to be remarkably safe. However, the very low risk of myopathy is substantially increased when simvastatin is given together with potent inhibitors of CYP3A4 While the overall safety record for simvastatin is exceptional, it would be desirable to further optimize its safety profile by reducing the potential for drug interactions with inhibitors of CYP3A4. It would also be desirable to further reduce the already low rate of occurrence of myopathy associated with the use of all statins. Statins are among the most widely used drugs in the world, and therefor the benefit of any further optimization of their safety profile would be significant.
One object of this invention is to minimize or eliminate the in vivo lactonization of a dihydroxy open-acid statin. For oral administration, the dihydroxy open-acid statin or a pharmaceutically acceptable salt or ester thereof is to be administered so as to minimize formation of lactonized statin and thereby minimize the amount of lactonized statin that is absorbed from the intestine while maximizing the amount of dihydroxy open-acid statin that is absorbed from the intestine.
Accordingly, this invention involves a method of inhibiting HMG-CoA reductase with an effective inhibitory amount of an orally dosed statin comprising delivering at least 90% of the dosed statin in its dihydroxy open acid form to the intestinal mucosa of a patient in need of such treatment.
The instant invention further provides a method for inhibiting HMG-CoA reductase, as well as for treating and/or reducing the risk for diseases and conditions affected by inhibition of HMG-CoA reductase, comprising orally administering a therapeutically effective amount of a compound selected from a dihydroxy open acid statin and a pharmaceutically acceptable salt or ester thereof in a delayed-release pharmaceutical dosage form to a patient in need of such treatment wherein substantial release of the compound from the dosage form is delayed until after passage of the dosage form through the stomach.
One embodiment of the first object is to provide the above-described method wherein the delayed-release pharmaceutical dosage form is a gel extrusion module (GEM) drug delivery device.
Another embodiment of the first object is to provide the above-described method wherein the delayed-release pharmaceutical dosage form is an enterically coated pharmaceutical dosage form. An additional aspect of this embodiment is to provide the above-described method wherein the delayed-release pharmaceutical dosage form is selected from an enterically coated rapid-release pharmaceutical dosage form and an enterically coated time controlled-release pharmaceutical dosage form. Yet another aspect of this embodiment is to provide the above-described method wherein the delayed-release pharmaceutical dosage form is an enterically coated gel extrusion module (GEM) drug delivery device.
The compound used for the above-described object and embodiments may particularly be dihydroxy open acid simvastatin and the pharmaceutically acceptable salts thereof, and more particularly a pharmaceutically acceptable salt thereof.
A second object of the instant invention is to provide novel HMG-CoA reductase inhibitors which are crystalline hydrated forms of the calcium salt of dihydroxy open acid simvastatin, and particularly the compound referred to herein as compound I.
Additional objects are to provide the use of the crystalline hydrated forms of the calcium salt of dihydroxy open acid simvastatin, particularly compound I, for inhibiting HMG-CoA reductase, as well as for treating and/or reducing the risk for diseases and conditions affected by inhibition of HMG-CoA reductase, and also to provide pharmaceutical formulations, including conventional rapid-release, delayed-release and time controlled-release formulations, including the GEM drug delivery device and enterically coated dosage forms, that can be used with the compounds. A further embodiment is to provide a composition and method for improving the long-term stability of a formulated drug product containing compound I by enterically coating a core tablet comprised of compound I with an enteric coating, particularly SURETERIC WHITE(copyright). A further object is to provide a process for making compound I. Additional objects will be evident from the following detailed description.